HER2, a member of the ErbB/HER receptor family, is overexpressed and/or deregulated in several cancers of the breast and ovary (King, Kraus and Aaronson, Science 1985; 229: 974-976; Slamon et al., Science 1989; 244:707-712). Therapeutics targeting HER2 have been used successfully in the clinic and have been approved by the US FDA. Such antibody therapeutics includes trastuzumab (Horton, Cancer Control 2001: 8(1), 103-110) and pertuzumab (Badache and Hynes, Cancer Cell; 5(4): 299-301). Several studies have indicated that therapeutic enhancement may be achieved by combining two or more epitope-distinct anti-HER2 antibodies such as trastuzumab and pertuzumab compared to a single antibody monotherapy (Kasprzyk et al., Cancer Res 1992; 52: 2771-2776, Ben-Kasus et al., Proc Natl Acad Sci USA, 106(9) 3294-3329). Trastuzumab which binds to the extracellular domain 4 of HER2 inhibits ligand independent signaling, stimulates ADCC, blocks HER2 shedding but does not inhibit HER2 dimerization. Pertuzumab which binds to the extracellular domain 2 inhibits HER2 dimerization and dimerization with other HER family receptors, inhibits multiple ligand-dependent HER mediated signaling pathways and stimulates ADCC (O'Sullivan and Connolly, Oncology 2014; 28(3): 186-194).
A combination of Pertuzumab and Trastuzumab for the treatment of HER2-positive metastatic cancer has been approved by FDA in 2013 as a new treatment for HER2-positive breast cancer, based on substantial clinical benefit seen over Trastuzumab alone (Baselga et al. N Engl J Med. 2012 Jan. 12; 366(2):109-19). However, the efficacy of the use of the simple combination of two or more monoclonal antibodies is sub-optimal. In addition, the cost of producing two or more monoclonal antibodies separately is high.
Therefore, there is a need to improve the efficacy of cancer treatment by combining monoclonal antibodies and reduce the cost associated with the monoclonal antibody productions.